Formulations of pharmaceutical compositions and processes for preparing them depend upon the properties of the active ingredient, the desired route of administration and the end use to be obtained.
Naloxone is a narcotic antagonist that prevents or reverses the effects of opioids. The compound and methods for its synthesis are described in U.S. Pat. No. 3,254,088. Its use as a narcotic antagonist is described in U.S. Pat. No. 4,267,182. A preferred route of administration of a narcotic antagonist is by the parenteral route (i.e. intravenous injection or infusion). The parenteral route of administration affords rapid delivery of the drug, complete bioavailability, and is more predictable and controllable than other routes. Solution formulations for parenteral administration must be essentially free of particulate matter, and they must be sterile. They must be physically and chemically stable, so that efficacy and safety are predictable.
Formulations for parenteral administration can be prepared as solutions that are ready to inject or ready to dilute with an infusion solution, or they can be prepared as dry powders that must be dissolved before use. Solution formulations are preferred over dry powders, when feasible, because of ease of use, ease of manufacture, and reduced cost.
U.S. Pat. No. 4,576,930 describes the stabilization of glucose solutions for intravenous infusion during autoclaving by addition of chelating agents, such as sodium edetate, to suppress thermal discoloration and decomposition of the glucose.
Instability of naloxone solution has been observed in the manufactured product. Autoclaving of currently available formulations of naloxone caused significant degradation of naloxone and formation of noroxymorphone. The degradation rates depended on headspace oxygen content. When non-autoclaved samples were sparged/flushed with nitrogen, no significant changes were observed in naloxone and bisnaloxone levels. However, noroxymorphone level increased from 0.08% to 0.4% over a six-week period at 60.degree. C. It has now been found that addition of a chelating agent, such as sodium edetate, to the commercial formulation prevents naloxone degradation, even in the presence of oxygen and after autoclaving.